This is the first revision of a competing continuation application to proceed with investigations of the effects of environmental stress and the subsequent activation of corticotropin-releasing hormone (CRH) and the hypothalamic-pituitary-adrenal (HPA) axis on intravenous cocaine self-administration in rats. The primary hypothesis underlying these experiments is that cocaine reinforcement is mediated, at least in part, through interactions with common neurobiological effector systems also activated by stress. Data collected through this project to date have demonstrated an important role for both CRH and corticosterone in cocaine reward. Compounds that suppress cocaine-induced increases in CRH or plasma corticosterone, or those that block physiological processes activated following exposure to stressors were shown to significantly attenuate ongoing cocaine self-administration as well as the reinstatement of extinguished cocaine-seeking behavior. During the requested period of this project, research will continue to focus on such compounds, further clarifying their acute effects on cocaine reinforcement. Research also will focus on the effects of rational combinations of these compounds on cocaine self-administration in an attempt to capitalize on the potential beneficial effects of these compounds while minimizing their adverse effects. Preliminary data suggest that such combinations are effective in reducing cocaine self-administration at doses that produce no apparent effects when administered separately. In addition, pharmacotherapies for the treatment of cocaine addiction are unlikely to ever routinely involve a "magic bullet" approach, whereby a drug is administered once and the addict is "cured" forever. Rather, future medications for the treatment of addiction will likely continue to require chronic dosing. However, most preclinical laboratories investigating potential therapeutic agents for drug abuse, including ours, typically evaluate several doses of the test compound following its acute administration only. A more valid approach would be to test these compounds under conditions more analogous to how they would be used in the clinic. Therefore, we propose to also investigate the chronic administration of these compounds under different conditions. The experiments described in this revised application were designed with these stipulations in mind, taking into consideration the recommendations of the reviewers of the previous submission.